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Genetically Modified Neural Stem Cells, Flucytosine, and Leucovorin for Treating Patients With Recurrent High-Grade Gliomas

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by City of Hope Medical Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT02015819
First received: December 13, 2013
Last updated: November 21, 2014
Last verified: November 2014
  Purpose

This phase I trial studies the side effects and determines the best dose of genetically modified neural stem cells and flucytosine when given together with leucovorin for treating patients with recurrent high-grade gliomas. Neural stem cells can travel to sites of tumor in the brain. The neural stem cells that are being used in this study were genetically modified express the enzyme cytosine deaminase (CD), which converts the prodrug flucytosine (5-FC) into the chemotherapy agent 5-fluorouracil (5-FU). Leucovorin may help 5-FU kill more tumor cells. The CD-expressing neural stem cells are administered directly into the brain. After giving the neural stem cells a few days to spread out and migrate to tumor cells, research participants take a 7 day course of oral 5-FC. (Depending on when a research participant enters the study, s/he may also be given leucovorin to take with the 5-FC.) When the 5-FC crosses into brain, the neural stem cells convert it into 5-FU, which diffuses out of the neural stem cells to preferentially kill rapidly dividing tumor cells while minimizing toxicity to healthy tissues. A Rickham catheter, placed at the time of surgery, will be used to administer additional doses of NSCs every two weeks, followed each time by a 7 day course of oral 5-FC (and possibly leucovorin). This neural stem cell-based anti-cancer strategy may be an effective treatment for high-grade gliomas.


Condition Intervention Phase
Adult Anaplastic Astrocytoma
Adult Anaplastic Oligodendroglioma
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Recurrent Adult Brain Tumor
Biological: E. coli CD-expressing genetically modified neural stem cells
Drug: flucytosine
Drug: leucovorin calcium
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Cytosine Deaminase-Expressing Neural Stem Cells in Combination With Oral 5-Fluorocytosine and Leucovorin for the Treatment of Recurrent High-Grade Gliomas

Resource links provided by NLM:


Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) and incidence of dose limiting toxicities (DLTs) [ Time Frame: Day 28 of course 1 ] [ Designated as safety issue: Yes ]
    Tables will be created to summarize all toxicities and side effects by dose, course, organ, severity assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 and attribution. Rates and associated 90% confidence limits will be estimated for the DLT rate at the MTD/MFD.

  • Incidence of all adverse events and toxicities [ Time Frame: Up to 28 days after the last infusion of NSCs ] [ Designated as safety issue: Yes ]
    Tables will be created to summarize all toxicities and side effects by dose, course, organ, severity assessed by NCI CTCAE version 4.0.

  • Clinically significant allergic reactions to NSCs [ Time Frame: Up to 28 days after the last infusion of NSCs ] [ Designated as safety issue: Yes ]
    Tables will be created to summarize all toxicities and side effects by dose, course, organ, severity assessed by NCI CTCAE version 4.0.

  • Mechanical issues with repeat administrations of NSCs via Rickham [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • T cell responses and antibodies against NSCs using T-cell receptor beta chain variable region (TcR Vbeta), CD 107 assays, and flow cytometry [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Development of a T cell response to the NSCs will be evaluated by a combination of TcR Vbeta spectratyping and CD1-7 degranulation assays using established laboratory SOP and protocols. Data from assessing for possible development of NSC immunogenicity with repeat exposure will be presented in an exploratory fashion using descriptive statistics and graphical methods.

  • Pharmacokinetic (PK) parameters (Tmax, Cmax, area under the curve [AUC], t 1/2) [ Time Frame: Baseline and on days 4-10 of course 1 ] [ Designated as safety issue: No ]
    PK data from the patients who undergo intracerebral microdialysis will be summarized using descriptive statistics and graphical methods. All summaries will be exploratory in spirit.

  • Ratio of the AUC of 5-FU in dialysate to plasma [ Time Frame: Baseline and on days 4-10 of course 1 ] [ Designated as safety issue: No ]
    PK data from the patients who undergo intracerebral microdialysis will be summarized using descriptive statistics and graphical methods.

  • Ratio of the AUC of flucytosine in dialysate to plasma [ Time Frame: Baseline and on days 4-10 of course 1 ] [ Designated as safety issue: No ]
    PK data from the patients who undergo intracerebral microdialysis will be summarized using descriptive statistics and graphical methods.

  • NSC biodistribution, specifically the area of NSC coverage [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Data from studying the distribution of NSCs in the brain via iron-labeling of the NSCs will be presented in an exploratory fashion using descriptive statistics and graphical methods.

  • Tumor response using the Macdonald Criteria [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Rates and associated 90% confidence limits will be estimated for the rate of clinical benefit.

  • Fate of NSCs, specifically NSC persistence [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Data from performing autopsies to determine the date of the NSCs will be presented in an exploratory fashion using descriptive statistics and graphical methods.


Estimated Enrollment: 24
Study Start Date: October 2014
Estimated Primary Completion Date: October 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (neural stem cells, flucytosine, leucovorin)
Patients receive CD-expressing neural stem cells intracranially on days 1 and 15. Flucytosine is taken orally every 6 hours on days 4-10 and 18-24. Depending on when a subject enters the study, s/he may also be given leucovorin orally every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Biological: E. coli CD-expressing genetically modified neural stem cells
Given intracranially
Other Name: HB1.F3.CD neural stem cells
Drug: flucytosine
Given orally
Other Names:
  • 5-FC
  • 5-fluorocytosine
  • Ro 2-9915
Drug: leucovorin calcium
Given orally
Other Names:
  • CF
  • CFR
  • LV
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To define the phase II recommended dose of intracerebrally administered cytosine deaminase (CD)-expressing neural stem cells (NSCs) in combination with oral 5-fluorocytosine (FC) (flucytosine) and leucovorin.

II. To determine the feasibility of treating study patients with more than 1 dose of NSCs followed by 7-day courses of 5-FC and leucovorin.

SECONDARY OBJECTIVES:

I. To assess for possible development of NSC immunogenicity (anti-NSC T cell and/or antibody response) with repeat doses of NSCs.

II. To characterize the relationship between intracerebral and systemic concentrations of 5-FC and 5-FU at the maximum tolerated dose level.

III. To evaluate the intracerebral distribution of NSCs using iron-labeling as a cellular tracker.

IV. To describe the clinical benefit (defined as stable disease, partial response, or complete response) of this treatment regimen.

V. To determine, at time of autopsy, the fate of the NSCs.

OUTLINE: This is dose-escalation study of CD-expressing genetically modified neural stem cells and flucytosine.

Patients receive CD-expressing neural stem cells intracranially (IC) on days 1 and 15 and flucytosine orally (PO) every 6 hours on days 4-10 and 18-24. Depending on when a subject enters the study, s/he may also be given leucovorin orally every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 30 days, 3 months, 6 months, 1 year, and then annually thereafter.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient has had a prior, histologically-confirmed, diagnosis of a grade IIII or IV glioma (including glioblastoma, anaplastic oligodendroglioma, or anaplastic astrocytoma, gliosarcoma, anaplastic oligodendroglioma, or anaplastic oligoastrocytoma), or has a prior, histologically-confirmed, diagnosis of a grade II glioma and now has radiographic findings consistent with a high-grade glioma (grade III or IV)
  • Imaging studies show evidence of recurrent, supratentorial tumor(s)
  • Patient's high-grade glioma has recurred or progressed after prior treatment with brain radiation and temozolomide
  • Patient has a Karnofsky performance status of >= 70%
  • Patient has a life expectancy of >= 3 months
  • Female patients of childbearing potential and sexually-active male patients must agree to use an effective method of contraception while participating in this study; women of childbearing potential must have a negative pregnancy test =< 2 weeks prior to registration
  • The patient must be in need of a craniotomy for tumor resection or a stereotactic brain biopsy for the purpose of diagnosis or differentiating between tumor progression versus treatment-induced effects following radiation therapy +/- chemotherapy
  • Based on the neurosurgeon's judgement, there is no anticipated physical connection between the post-resection tumor cavity and the cerebral ventricles
  • Absolute neutrophil count (ANC) >= 1500 cells/mm^3
  • Platelet count >= 100,000 cells/mm^3
  • Total bilirubin =< 2.0 mg/dl
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 4 times the institutional upper limit of normal
  • Serum creatinine =< the institutional upper limit of normal
  • There is no limit to the number of prior therapies
  • All subjects must have the ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

  • Patient has anti-human leukocyte antigen (HLA) antibodies specific for HLA antigens expressed by the NSCs
  • Patient has not recovered from any toxicity of prior therapies; an interval of

    • At least 6 weeks must have elapsed since taking a nitrosourea-containing chemotherapy regimen
    • At least 4 weeks since completing a non-nitrosourea-containing cytotoxic chemotherapy regimen
    • At least 2 weeks from taking the last dose of targeted agent
    • At least 4 weeks from the last dose of bevacizumab
  • Patient is unable to undergo a magnetic resonance imaging (MRI)
  • Patient is allergic to 5-FC, leucovorin, or 5-FU
  • Patient has chronic or active viral infections of the central nervous system (CNS)
  • Patient has a coagulopathy or bleeding disorder
  • Patient has an uncontrolled illness including ongoing or active infection
  • Patient is receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy
  • Patient has had prior therapy with neural stem cells
  • Patient is pregnant or breast feeding; pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is participating in this study
  • Patient has another active malignancy
  • Non-compliance; a patient has a serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the safety monitoring requirements and completion of treatment according to this protocol
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02015819

Locations
United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Alexandra Ching, NP    626-471-9393    neurosurgery@coh.org   
Principal Investigator: Jana Portnow, MD         
Sponsors and Collaborators
City of Hope Medical Center
Investigators
Principal Investigator: Jana Portnow City of Hope Medical Center
  More Information

No publications provided

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT02015819     History of Changes
Other Study ID Numbers: 13401, NCI-2013-02346, 13401
Study First Received: December 13, 2013
Last Updated: November 21, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Astrocytoma
Glioblastoma
Gliosarcoma
Oligodendroglioma
Glioma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Flucytosine
Levoleucovorin
Anti-Infective Agents
Antidotes
Antifungal Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014